MEAction 2021 MECFS researchers video with R Davis,Prusty

[Ravn]

Can't recall if it was in this or some other recent video that Ron Davis said they were making all their data - including unpublished (I think, memory...) - available to other researchers. That would be one way of overcoming the lack of urgency to publish by OMF themselves; those other researchers are very likely using the data with view of publication.

Would be nice though to know who those other researchers are, what they're looking at and how far away they're from publishing.

 

[ME/CFS Skeptic]

Janet says that 70 patients have been tested for the IDO2 mutation and all but one (who is an 'unusual case') has the mutation.

(Has this been replicated by any other researcher?

The main issue I have with the tryptophan trap hypothesis is that thus far there doesn't seem to be a reason to think it has anything to do with ME/CFS. So if they have data suggesting this IDO2 mutation is more common in ME/CFS patients that would be a first step. If they publish these results, other ME/CFS research could probably quickly test this in their ME/CFS patient sample as well.

I think that is more indicated than experimenting with yeast cells.

 

[Andy]

Can't recall if it was in this or some other recent video that Ron Davis said they were making all their data - including unpublished (I think, memory...) - available to other researchers. That would be one way of overcoming the lack of urgency to publish by OMF themselves; those other researchers are very likely using the data with view of publication.

As I pointed out in the other thread that discussed this, the other researchers have to know that OMF have the data though and that it is available. That is a lot more obvious, especially to researchers who aren't already part of the 'scene', if its in the existing publication system.

 

[cassava7]

The main issue I have with the tryptophan trap hypothesis is that thus far there doesn't seem to be a reason to think it has anything to do with ME/CFS. So if they have data suggesting this IDO2 mutation is more common in ME/CFS patients that would be a first step. If they publish these results, other ME/CFS research could probably quickly test this in their ME/CFS patient sample as well.

I think that is more indicated than experimenting with yeast cells.

Ron Davis and Robert Phair might have specific reasons for not publishing data on IDO2 sequencing in the cohort of patients at Stanford, but they and their team have held onto the results of those 70 patients since at least late 2019 (or even mid-2019).

A plausible guess is that they mean to test more patients for statistical purposes before publishing, but that the pandemic has prevented them to do so (and they are instead forced to experiment in the lab for now).

In the medium to long term, OMF runs the risk of having a scarce legacy because of its policy of not publishing regularly, which is problematic given that it is the main privately-funded ME/CFS research organization. In particular, I am afraid that it will struggle as a whole when Ron Davis will (have to) cease working on his research. This could be offset by bringing in early career researchers, which OMF is trying to do, but infrequent research output is the opposite of what they need to advance in their academic career and will turn them away.

On the other hand, publication is also limited by OMF's limited resources, including manpower, which inevitably result in slow progress.

 

[Hutan]

Ron Davis and Robert Phair might have specific reasons for not publishing data on IDO2 sequencing in the cohort of patients at Stanford, but they and their team have held onto the results of those 70 patients since at least late 2019 (or even mid-2019).

A plausible guess is that they mean to test more patients for statistical purposes before publishing, but that the pandemic has prevented them to do so (and they are instead forced to experiment in the lab for now).

Yeah, I'm just not buying that as a reasonable excuse if the aim is to move this tryptophan hypothesis forward as quickly as possible. They could have commissioned the UK ME/CFS biobank to do a study on the IDO2 mutations for the samples already to hand. They could have worked with an Australian or New Zealand researcher, or talked to Emerge (all largely unaffected by Covid-19) about getting samples and evaluating the IDO2 gene. OMF could still do those things. It's not a complicated study, or one that would take long to do.

Presumably DecodeME will give a definitive answer - I'm not sure how far away that is.

I think that is more indicated than experimenting with yeast cells.

I totally agree - if the IDO2 idea doesn't hold up, then it's research money and time wasted.

 

[cassava7]

Yeah, I'm just not buying that as a reasonable excuse if the aim is to move this tryptophan hypothesis forward as quickly as possible. They could have commissioned the UK ME/CFS biobank to do a study on the IDO2 mutations for the samples already to hand. They could have worked with an Australian or New Zealand researcher, or talked to Emerge (all largely unaffected by Covid-19) about getting samples and evaluating the IDO2 gene. OMF could still do those things. It's not a complicated study, or one that would take long to do.

Presumably DecodeME will give a definitive answer - I'm not sure how far away that is.

Yes, it seems strange to me that they haven't done so already. OMF's communication on their research progress is opaque and the news they give are often rehashed.

ETA: I believe donors and the ME/CFS patient community would much welcome candid monthly updates on OMF's work, and would be the first to be understanding of "behind the scenes" struggles with ongoing research projects.

 

[Andy]

Presumably DecodeME will give a definitive answer - I'm not sure how far away that is.

All depends on how quickly we reach our 20k sample target, that is the thing that will take the most amount of time once we get going as, in the grand scheme of things, analysis of the data wont take that long. We are scheduled to run until Sep 2024 but we are hopeful of getting results out sooner than that, the amazing response so far from the community makes us cautiously optimistic that we will be ahead of schedule but we aren't, and can't, making any promises at this stage.

 

[Milo]

Ron Davis and Robert Phair might have specific reasons for not publishing data on IDO2 sequencing in the cohort of patients at Stanford, but they and their team have held onto the results of those 70 patients since at least late 2019 (or even mid-2019).

A plausible guess is that they mean to test more patients for statistical purposes before publishing, but that the pandemic has prevented them to do so (and they are instead forced to experiment in the lab for now).

In the medium to long term, OMF runs the risk of having a scarce legacy because of its policy of not publishing regularly, which is problematic given that it is the main privately-funded ME/CFS research organization. In particular, I am afraid that it will struggle as a whole when Ron Davis will (have to) cease working on his research. This could be offset by bringing in early career researchers, which OMF is trying to do, but infrequent research output is the opposite of what they need to advance in their academic career and will turn them away.

On the other hand, publication is also limited by OMF's limited resources, including manpower, which inevitably result in slow progress.

I agree, and do you remember the severely ill study? It started in 2015 or 2016. I feel that it is disrespectful to the subjects to not publish.

 

[Barry]

Ron says that researchers should focus their efforts on what helps the patients, and not on publication.

If nothing is published, most drugs cannot be prescribed off-label here in Canada. No publication, no evidence the drug works, drug is not covered.

No publication, if that really is policy, is also likely to put off good researchers, especially early career researchers, since their careers depend on publication records unless they are tenured, which many aren't.

I don't think Ron Davis was suggesting to not publish, but simply not put the cart before the horse when it comes to motivation. Not: What can I research that will bring me fame and fortune once I publish. But: What can I research that will benefit humanity, and then publish once the time is right. Ron Davis is not going to be someone to misunderstand the importance of publishing, he just gets bugged by people who think science is primarily about eminence-gaining publications.

 

[Snow Leopard]

24.30 Tryptophan trap Ron says that the community have got confused, thinking that the tryptophan is in the serum, but it's actually the levels that are made in the immune cells that matter. In an infection, the tryptophan is released from the albumin which is then broken down to kynurunine. The enzyme that breaks down the tryptophan is IDO1, but if the level of tryptophan is too high, IDO1 doesn't work. In most people, they have another enzyme, IDO2, that works at high levels of tryptophan. But, if there is a mutation in IDO2 that makes it dysfunctional, high levels of tryptophan make a metabolic trap - there isn't a way to break down the tryptophan. Janet says that 70 patients have been tested for the IDO2 mutation and all but one (who is an 'unusual case') has the mutation.

The problem is even this hypothesis (IDO2 dysfunction in immune cells), this still doesn't explain ME/CFS symptoms at all. There is too much missing in their hypothesis at the moment.

I also don't agree with the reasons given for not publishing their data. Reading between the lines, it almost seems like an admission their data is too weak to be published in a decent journal. If they want to prove me wrong, publish it (as a preprint or in a journal)...

 

[Andy]

I don't think Ron Davis was suggesting to not publish, but simply not put the cart before the horse when it come to motivation. Not: What can I research that will bring me fame and fortune once I publish. But: What can I research that will benefit humanity, and then publish once the time is right. Ron Davis is not going to be someone to misunderstand the importance of publishing, he just gets bugged by people who think science is primarily about eminence-gaining publications.

But when will the time be right for him to publish? When the star's align? And I could care less about whether he gains eminence from a publication or not, I want him to publish so that what he has found can be used by as many other researchers as possible, and so that it can help as many patients as possible.

 

[Milo]

But when will the time be right for him to publish? When the star's align? And I could care less about whether he gains eminence from a publication or not, I want him to publish so that what he has found can be used by as many other researchers as possible, and so that it can help as many patients as possible.

I very much agree with you @Andy . New to the field researchers would do a deep review of the literature. If it’s not in the literature, then it has not been done. Scientists communicate via scientific publication, and must be replicated. Also it seems to me that OMF has collaborators from all continents, and it is unclear to me whether they only share data with these folks or they also share to others as well.

i do not want to discredit the work of OMF or Dr Davis, they have done some good work. However we have not seen results from this effort, of what i can remember.

Edit to add: Of course COVID came some 15 months ago and it tampered with the ability to continue doing lab work and other research activities. However, paper writing would have been one of the activities that could have been done during that time.

 

[dreampop]

I'm a little surprised metabolic trap progress has been slow. It's worth noting that OMF recieved a $1M donation specific for the metablic trap hypothesis in mid-2018.




They recieved $5M in 2017 due to a bitcoin billionaire.

https://www.omf.ngo/pineapple-fund/

And $2M in late 2019.

https://www.omf.ngo/thank-you-to-donors/

$4.5M in 2020

https://www.omf.ngo/4-5m-raised-in-2020-your-donations-at-work/

And they just had a may 2021 donation drive.

Most of the 5 I believe went to seeding the OMF at Harvard, Uppsala, Montreal and Melbourne (although I think the last 2 are fairly small) but I believe they have raised more ontop of these donations. I had a brief look over their financial data and noted substantial donor restrictions - I'm not sure what that means, but they seem in good financial health. They had about $1M in grants as well in 2019.

I'm not trying to be critical of the OMF, I appreciate their work greatly. But in that context, I'm surprised that so little has made it's way into published form.

 

[dreampop]

I actually came across this on the OMF site, I had never heard of before - basically a nitrogen trap.

https://www.omf.ngo/nitrogen-metabolism-and-testing-nitrogen-hypothesis-in-me-cfs/

We hypothesize that toxic nitrogen-containing by-products of energy metabolism accumulate more readily in the cells of ME/CFS patients. This accumulation, in turn, creates a cycle of energy generation to overcome a stressed state while generating more toxic nitrogen by-products in the process. We will also identify the compounds that can circumvent the production of toxic nitrogen by-products and release patients from this cycle.

You can take a look at all their projects about half way down their webpage, there is quite a bit going on.

https://www.omf.ngo/the-end-mecfs-project/

 

[Trish]

I think they have underestimated how long it takes to get research done, written up, peer reviewed, altered according to recommendations of peer reviewers and published. There are always hitches along the way, like staff who are key to projects moving on to other jobs and needing to appoint new people, staff working on other projects at the same time, and in the case of a lot of the work Ron's team does, needing to design, test and get manufactured new pieces of equipment. All that takes a huge amount of time and money. I think Ron Davis said that they were using the time out of the lab because of Covid to do some writing up of results for publication.

 

[FMMM1]

I've done a transcript of Dr. Bhupesh Prusty's interview, using the subtitles from Youtube.

Main take-aways for me were that he received two grants for these two projects:

1. A two-year project, funded by ME Research UK with ~270,000 GBP, with a focus on finding "autoantibodies that can target mitochondria for dysfunction"

2. A three-year project, funded by Amar Foundation (US) with 900,000 US$, with a focus on a "unique experimental approach" to "understand long-covid and the relationship of long-covid with ME/CFS"

According to Dr. Prusty, science is "on the right path" and he suspects some exciting developments in the next 3-5 years.

Bhupesh mentions a publication in Nature last year and a technique - slum seq ? Anyone know what this is?

We published a paper in [the journal] 'Nature' last year. This technology is called [slum seq ?]. It's basically - what we will do is, that we will understand the different pathways going on inside the cells at the single cell level.

 

[FMMM1]

I can see what you are saying, I agree with it even. But what we are seeing from OMF, and also from the Stanford clinical team that has been promoting Abilify, is research that isn't robust enough to tell people outside of the Stanford bubble if there is really something worth pursuing. We just have anecdotal evidence that Abilify helped Whitney. The unblinded Abilify study from the clinical team did nothing to bring clarity.

I get that Ron feels compelled to move swiftly to find something to cure his son, and that creates an incentive to work differently. But, a robust finding (regarding Abilify and/or the IDO2 mutation prevalence) would either rapidly bring more researchers and more funders on board and probably make progress quicker, or make it clear that the community's research funds would be better targeted elsewhere. Neither study would be terribly expensive.

I'm sure that we aren't getting the whole story and I hope that things are more solid than they seem from here. A paper with a real finding would do a lot to establish OMF's credibility. It need not take much of Ron's time - the OMF board could just use some of their funding to get an independent research team to do a study. I suspect that with OMF's social media reach, they could probably even fund such a study largely by crowd funding.

Perhaps one for @Simon M. Would Chris Ponting's GWAS study establish whether the mutation of IDO2 you carry is relevant in terms of ME/CFS? E.g. if a copy that is non-functioning increases your chances of developing ME/CFS and/or a copy which produces functional IDO2 reduces your chances of developing ME/CFS? In effect would Chris's study test the metabolic trap theory?

 

[FMMM1]

They seem vested in the IDO2 metabolic trap hypothesis, maybe a little too much in my view. I still haven't learned why they decided to pick that particular gene and mutation out of the tens of thousands of other genes. Even if they only consider genes that could create a bistable system and metabolic trap, Phair has already mentioned there are several other candidates.

The other question is how it ties into the Abilify improvements, which seems hard to understand. If they believe that the metabolic trap is the cause of the disease and that Abilify improves patients, then you'd think Abilify would affect kynurenine or tryptophan pathways in some way, but everything we hear is that it primarily affects dopamine.

I also think they should publish more. Actually, this paper from Moreau et al. who collaborate with OMF is in the 99th percentile of all articles of similar age according to metrics, so clearly such articles can have a big impact.

I think the identification of IDO2 is well documented i.e. Robert Phair looked carefully at a small number of genomes* and identified that all had an IDO2 gene which was "defective" i.e. produced a form of the enzyme which wouldn't work/be expected to work properly. The odds of all having an IDO2 gene which was "defective" were really low. There's quite a bit about it on Phoenix and I think @Perrier may have been a contributor/commentator there.

EDIT - I think the statement about high plasma levels of kynurenine(?) not being relevant, i.e. due to low transportation rate into the cell, is interesting - may not be relevant of course.

*about 10 severely ill people? - Janet mentions the current number - still really small (70?).

 

[FMMM1]

Ron Davis and Robert Phair might have specific reasons for not publishing data on IDO2 sequencing in the cohort of patients at Stanford, but they and their team have held onto the results of those 70 patients since at least late 2019 (or even mid-2019).

I think the key thing, as @Michiel Tack has indicated, is to identify the role of IDO2 via a larger study e.g. Chris Ponting's GWAS study. The "70" number quoted looks impressive but could it be selection bias? If the role of IDO2 cannot be identified via GWAS (perhaps because OMF have selected a sub-group) then the results are not necessarily useless but you'd then need to think --- why only this group -- and --- is the finding relevant to the wider patient population--?

I actually think the research is interesting but it hasn't progressed quickly. OK the yeast work e.g. looks like a potential way to examine whether particular mutations in IDO2 produce functional enzyme but it's too early to say the IDO2 theory is relevant.

I actually find the link to abilify interesting -makes me wonder if the research could help to explain the basis of common "psychiatric" [may not be the best word] illnesses.

 

[FMMM1]

Yeah, I'm just not buying that as a reasonable excuse if the aim is to move this tryptophan hypothesis forward as quickly as possible. They could have commissioned the UK ME/CFS biobank to do a study on the IDO2 mutations for the samples already to hand. They could have worked with an Australian or New Zealand researcher, or talked to Emerge (all largely unaffected by Covid-19) about getting samples and evaluating the IDO2 gene. OMF could still do those things. It's not a complicated study, or one that would take long to do.

Presumably DecodeME will give a definitive answer - I'm not sure how far away that is.


I totally agree - if the IDO2 idea doesn't hold up, then it's research money and time wasted.

I wonder if Aptamers are a way of determining intracellular tryptophan concentrations - thereby testing whether intracellular levels are high (trap). Aptamers give very good (low) detection limits. Sure OMF have thought of that though i.e. since they have Maureen Hanson* and Jonas Berquist on the team (among others).

*Maureen Hanson's - publication used Aptamers file:///C:/Users/USER%201/Downloads/proteomes-09-00006%20(3).pdf